Publications by authors named "Jianjun Shen"

104 Publications

ATF3-Induced Mammary Tumors Exhibit Molecular Features of Human Basal-Like Breast Cancer.

Int J Mol Sci 2021 Feb 26;22(5). Epub 2021 Feb 26.

Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Science Park, Smithville, TX 78957, USA.

Basal-like breast cancer (BLBC) is an aggressive and deadly subtype of human breast cancer that is highly metastatic, displays stem-cell like features, and has limited treatment options. Therefore, developing and characterizing preclinical mouse models with tumors that resemble BLBC is important for human therapeutic development. is a potent oncogene that is aberrantly expressed in most human breast cancers. In the BK5.ATF3 mouse model, overexpression of in the basal epithelial cells of the mammary gland produces tumors that are characterized by activation of the Wnt/β-catenin signaling pathway. Here, we used RNA-Seq and microRNA (miRNA) microarrays to better define the molecular features of BK5.ATF3-derived mammary tumors. These analyses showed that these tumors share many characteristics of human BLBC including reduced expression of , , and and increased expression of , , and the genes encoding keratins 5, 6, and 17. An analysis of miRNA expression revealed reduced levels of and , leading to the upregulation of their target genes including both the pluripotency factors and as well as the cancer stem-cell-related gene . Finally, we show through knock-down experiments that may directly modulate expression. Taken together, our results indicate that the mouse mammary tumor model could provide a powerful model to define the molecular mechanisms leading to BLBC, identify the factors that contribute to its aggressiveness, and, ultimately, discover specific genes and gene networks for therapeutic targeting.
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http://dx.doi.org/10.3390/ijms22052353DOI Listing
February 2021

Celastrol Loaded Nanoparticles With ROS-Response and ROS-Inducer for the Treatment of Ovarian Cancer.

Front Chem 2020 30;8:574614. Epub 2020 Oct 30.

Department of Radiation Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.

Ovarian cancer is a gynecological cancer from which it is difficult to be completely cured. It is common to use regimens as an effective treatment for ovarian cancer, but these inevitably bring serious side effects. New treatment strategies and special drugs are needed to improve the prognosis of patients. Celastrol is a natural product, isolated from traditional medicine, that has been proven to be curative for inflammation and cancers. However, the non-targeting and low solubility of celastrol limit its clinical application. We prepared celastrol-loaded nanoparticles for the efficient treatment of ovarian cancer via oxidative stress amplification. In this work, a tumor-targeted, ROS-sensitive nanoparticle was designed, synthesized, and assembled into a drug delivery system that used celastrol. Folic acid (FA) groups on the surface of nanoparticles guide them to actively target the surface of the tumor cell membrane. Thioketal (TK) bonds in nanoparticles can be oxidized and broken into -SH within the ROS level of tumor tissues, which causes the breaking of the PEG hydrophilic shell layer of nanoparticles and promotes the release of celastrol. The released celastrol further stimulated the production of ROS and amplified the intracellular ROS level to promote the apoptosis of tumor cells, thus achieving a therapeutic effect on the celastrol treated ovarian cancer.
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http://dx.doi.org/10.3389/fchem.2020.574614DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662441PMC
October 2020

Transcriptional Activation of MYC-Induced Genes by GCN5 Promotes B-cell Lymphomagenesis.

Cancer Res 2020 Dec 9;80(24):5543-5553. Epub 2020 Nov 9.

Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, Texas.

Overexpression of the MYC oncoprotein is an initiating step in the formation of several cancers. MYC frequently recruits chromatin-modifying complexes to DNA to amplify the expression of cancer-promoting genes, including those regulating cell cycle, proliferation, and metabolism, yet the roles of specific modifiers in different cancer types are not well defined. Here, we show that GCN5 is an essential coactivator of cell-cycle gene expression driven by MYC overexpression and that deletion of delays or abrogates tumorigenesis in the mouse model of B-cell lymphoma. Our results demonstrate that loss impacts both expression and downstream functions of Myc. SIGNIFICANCE: Our results provide important proof of principle for Gcn5 functions in formation and progression of Myc-driven cancers, suggesting that GCN5 may be a viable target for development of new cancer therapies.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-2379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744430PMC
December 2020

Assessing cognitive load in adolescent and adult students using photoplethysmogram morphometrics.

Cogn Neurodyn 2020 Oct 14;14(5):709-721. Epub 2020 Jul 14.

Institute of Education, Tsinghua University, Beijing, China.

Compared to cardiac parameters and skin conductivities, the photoplethysmogram (PPG) recorded at fingertips and other parts near to peripheral nerve ends have been recently revealed to be yet another sensitive measure for cognitive load assessment. However, there is so far no research on measuring adolescents' cognitive load using physiological signals. A comprehensive study on the effects of PPG morphometrics over a cohort covering both adolescent and adult students is also absent. In this study, we analyze the morphological features of PPG on cognitive load assessment and compare them between adolescent and adult students. Experiments on two-level arithmetic tasks show that the PPG morphometrics reached the same level of significance on the effect of task difficulty/period as heart rate, and different morphological behaviors were also shown between adolescent and adult students during the cognitive task effects, which may imply their physiological differences across age. Physiological signals recorded by wearable devices are also found to be effective in measuring cognitive load.
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http://dx.doi.org/10.1007/s11571-020-09617-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7501395PMC
October 2020

Actin R256 Mono-methylation Is a Conserved Post-translational Modification Involved in Transcription.

Cell Rep 2020 09;32(13):108172

Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, Tyler, TX 75708, USA. Electronic address:

Nuclear actin has been elusive due to the lack of knowledge about molecular mechanisms. From actin-containing chromatin remodeling complexes, we discovered an arginine mono-methylation mark on an evolutionarily conserved R256 residue of actin (R256me1). Actin R256 mutations in yeast affect nuclear functions and cause diseases in human. Interestingly, we show that an antibody specific for actin R256me1 preferentially stains nuclear actin over cytoplasmic actin in yeast, mouse, and human cells. We also show that actin R256me1 is regulated by protein arginine methyl transferase-5 (PRMT5) in HEK293 cells. A genome-wide survey of actin R256me1 mark provides a landscape for nuclear actin correlated with transcription. Further, gene expression and protein interaction studies uncover extensive correlations between actin R256me1 and active transcription. The discovery of actin R256me1 mark suggests a fundamental mechanism to distinguish nuclear actin from cytoplasmic actin through post-translational modification (PTM) and potentially implicates an actin PTM mark in transcription and human diseases.
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http://dx.doi.org/10.1016/j.celrep.2020.108172DOI Listing
September 2020

Defining the mutation signatures of DNA polymerase θ in cancer genomes.

NAR Cancer 2020 Sep 27;2(3):zcaa017. Epub 2020 Aug 27.

School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan 44919, Republic of Korea.

DNA polymerase theta (POLQ)-mediated end joining (TMEJ) is a distinct pathway for mediating DNA double-strand break (DSB) repair. TMEJ is required for the viability of -mutated cancer cells. It is crucial to identify tumors that rely on POLQ activity for DSB repair, because such tumors are defective in other DSB repair pathways and have predicted sensitivity to POLQ inhibition and to cancer therapies that produce DSBs. We define here the -associated mutation signatures in human cancers, characterized by short insertions and deletions in a specific range of microhomologies. By analyzing 82 COSMIC (Catalogue of Somatic Mutations in Cancer) signatures, we found that -mutated cancers with a higher level of expression have a greatly enhanced representation of the small insertion and deletion signature 6, as well as single base substitution signature 3. Using human cancer cells with disruptions of , we further show that TMEJ dominates end joining of two separated DSBs (distal EJ). Templated insertions with microhomology are enriched in POLQ-dependent distal EJ. The use of this signature analysis will aid in identifying tumors relying on POLQ activity.
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http://dx.doi.org/10.1093/narcan/zcaa017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454005PMC
September 2020

Noninvasive Assessment of Epidermal Genomic Markers of UV Exposure in Skin.

J Invest Dermatol 2021 Jan 15;141(1):124-131.e2. Epub 2020 Jun 15.

Department of Tumor Biology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA; Donald A. Adam Melanoma & Skin Cancer Center of Excellence, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA; Department of Anatomic Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA. Electronic address:

The measurement of UV-induced DNA damage as a dosimeter of exposure and predictor of skin cancer risk has been proposed by multiple groups. Although UV-induced mutations and adducts are present in normal-appearing UV-exposed epidermis, sampling normal nonlesional skin requires noninvasive methods to extract epidermal DNA for analysis. Here, we demonstrate the feasibility of such an approach, termed surfactant-based tissue acquisition for molecular profiling. Sampling in patients was performed using a felt-tip pen soaked in a mixture of surfactants (Brij-30/N-decyl-N,N-dimethyl-3-ammonio-1-propanesulfonate). In mice, we show that the epidermis can be selectively removed without scarring, with complete healing within 2 weeks. We exposed hairless mice to low-dose UV radiation over a period of 3 months and serially sampled them through up to 2 months following the cessation of UV exposure, observing a progressive increase in a UV signature mutational burden. To test whether surfactant-based tissue acquisition for molecular profiling could be applied to human patients, samples were collected from sun-exposed and sun-protected areas, which were then subjected to high-depth targeted exome sequencing. Extensive UV-driven mosaicism and substantially increased mutational loads in sun-exposed versus sun-protected areas were observed, suggesting that genomic measures, as an integrated readout of DNA damage, repair, and clonal expansion, may be informative markers of UV exposure.
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http://dx.doi.org/10.1016/j.jid.2020.05.093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736225PMC
January 2021

The predictive ability of carotid artery corrected flow time and respirophasic variation in blood flow peak velocity measured by ultrasonography for fluid responsiveness in parturients for cesarean delivery.

Minerva Anestesiol 2020 Oct 12;86(10):1039-1046. Epub 2020 Jun 12.

Department of Anesthesiology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China -

Background: Ultrasonic measurements of carotid artery corrected flow time (FTc) and respirophasic variation in blood flow peak velocity (ΔVpeak) were recently introduced to predict fluid responsiveness in non-obstetric patients. We designed the present study to evaluate the performance of these two ultrasonic indices in predicting fluid responsiveness in healthy parturients.

Methods: Seventy-five parturients undergoing elective cesarean delivery were enrolled. Carotid doppler parameters including FTc, ΔVpeak, the inferior vena cava diameter at the end of expiration (IVCexp) and inspiration (IVCins), Inferior Vena Cava Collapsibility Index (IVCCI), and Stroke Volume Index (SVI) were measured before and after fluid challenge. Fluid responsiveness was defined as a 15% or more increase in SVI as assessed by transthoracic echocardiography after the fluid challenge.

Results: FTc and ΔVpeak but not IVCins, IVCexp and IVCCI were proved to be two independent predictors for fluid responsiveness by multivariate logistic regression, with the odds ratios of 1.191 (95% confidence interval (CI), 1.070 to 1.326) and 0.521 (95% CI, 0.351 to 0.773). The area under the ROC curve to predict fluid responsiveness for FTc was 0.846 (95% CI, 0.751-0.940) and for ΔVpeak was 0.810 (95% CI, 0.709-0.910), which were significantly higher than those for IVCins (0.436, 95% CI, 0.300-0.572), IVCexp (0.595, 95% CI, 0.460-0.730) and IVCCI (0.548, 95% CI, 0.408-0.688).

Conclusions: Compared with IVCins, IVCexp and IVCCI, FTc and ΔVpeak measured by ultrasonography seem to be the highly feasible and reliable methods to predict fluid responsiveness in parturients with spontaneous breathing undergoing elective cesarean delivery.
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http://dx.doi.org/10.23736/S0375-9393.20.14315-3DOI Listing
October 2020

Tetramethylpyrazine Attenuated Sevoflurane-Induced Neurotoxicity by Enhancing Autophagy through GPR50/CREB Pathway in SH-SY5Y Cells.

Am J Chin Med 2020 30;48(4):945-966. Epub 2020 May 30.

Department of Anesthesiology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, P. R. China.

Tetramethylpyrazine has shown neuroprotective and axonal outgrowth-promoting effects and can improve cognitive deficit in a rat model of chronic hypoperfusion. However, the role of tetramethylpyrazine in sevoflurane-induced neurotoxicity is still vague. Therefore, this study was designed to investigate the effects and mechanisms of tetramethylpyrazine on sevoflurane-induced autophagy, apoptosis, and the expression of BACE1 and A[Formula: see text] in SH-SY5Y cells. We measured the expression levels of the apoptosis protein markers Bax and Bcl-2, autophagy protein markers Atg5 and LC3-II, BACE1, and A[Formula: see text] in SH-SY5Y cells after sevoflurane treatment and determined the effects of tetramethylpyrazine on sevoflurane-induced expression of these proteins after silencing GPR50 or Atg5 with siRNA . We found that exposure to 3.4% sevoflurane for 6 h decreased the expression of autophagy protein markers and increased the expression of the apoptosis protein markers, BACE1, and A[Formula: see text] in SH-SY5Y cells. The number of red puncta (autolysosomes) and yellow puncta (autophagosomes) in each SH-SY5Y cell decreased after transient transfection with the mRFP-GFP-LC3 expression plasmid. Silencing of GPR50 decreased the expression of pCREB, Atg5, and LC3-II, while silencing of Atg5 increased the expression of BACE1 and A[Formula: see text] in SH-SY5Y cells. Our results demonstrate that tetramethylpyrazine attenuated sevoflurane-induced neurotoxicity by enhancing autophagy through the GPR50/CREB pathway in SH-SY5Y cells.
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http://dx.doi.org/10.1142/S0192415X20500457DOI Listing
September 2020

Evaluation of 2 ultrasonic indicators as predictors of difficult laryngoscopy in pregnant women: A prospective, double blinded study.

Medicine (Baltimore) 2020 Jan;99(3):e18305

Department of Anesthesia, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province.

Background: Ultrasonic measurements of tongue thickness and condylar translation were recently introduced to predict difficult laryngoscopy in non-obstetric patients. We designed the present study to evaluate the performance of these two ultrasonic indicators in predicting difficult laryngoscopy in healthy parturients.

Methods: The 119 parturients undergoing elective cesarean delivery were enrolled. Tongue thickness and condylar translation measured by ultrasonography, and Modified Mallampati test (MMT) score, inter-incisor distance (IID) and modified Cormack-Lehane grading system (MCLS) were measured and recorded before anesthesia. The primary outcome was difficult laryngoscopy defined as MCLS 3 or 4. The association between these variables and difficult laryngoscopy were analyzed by using multivariable logistic regression and receiver operating characteristic (ROC) curve.

Results: Compared to the Easy Laryngoscopy Group, the tongue thickness was significantly higher and the condylar translation and IID were significantly lower in the Difficult Laryngoscopy Group. Tongue thickness and condylar translation but not MMT score and IID were proved to be two independent predictors for difficult laryngoscopy by multivariate logistic regression, with the odds ratios of 2.554 (95% confidence interval (CI), 1.715 to 3.802) and 0.457 (95% CI, 0.304 to 0.686). The area under the ROC curve to predict difficult laryngoscopy for tongue thickness was 0.93 (95% CI, 0.88-0.98) and for condylar translation was 0.77 (95% CI, 0.67-0.86), which were significantly higher than those for MMT score (0.67, 95% CI, 0.56-0.77) and IID (0.65, 95% CI, 0.55-0.76).

Conclusions: Compared with MMT and IID, tongue thickness and condylar translation measured by ultrasonography appear to be better indicators for predicting difficult laryngoscopy in parturients.The trial was registered at the Chinese Clinical Trial Registry (ChiCTR)(www.chictr.org), registration number ChiCTR-ICR-1800019991.
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http://dx.doi.org/10.1097/MD.0000000000018305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7220303PMC
January 2020

Multisite Evaluation of Next-Generation Methods for Small RNA Quantification.

J Biomol Tech 2020 07;31(2):47-56

MIT BioMicro Center, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

Small RNAs (smRNAs) are important regulators of many biologic processes and are now most frequently characterized using Illumina sequencing. However, although standard RNA sequencing library preparation has become routine in most sequencing facilities, smRNA sequencing library preparation has historically been challenging because of high input requirements, laborious protocols involving gel purifications, inability to automate, and a lack of benchmarking standards. Additionally, studies have suggested that many of these methods are nonlinear and do not accurately reflect the amounts of smRNAs . Recently, a number of new kits have become available that permit lower input amounts and less laborious, gel-free protocol options. Several of these new kits claim to reduce RNA ligase-dependent sequence bias through novel adapter modifications and to lessen adapter-dimer contamination in the resulting libraries. With the increasing number of smRNA kits available, understanding the relative strengths of each method is crucial for appropriate experimental design. In this study, we systematically compared 9 commercially available smRNA library preparation kits as well as NanoString probe hybridization across multiple study sites. Although several of the new methodologies do reduce the amount of artificially over- and underrepresented microRNAs (miRNAs), we observed that none of the methods was able to remove all of the bias in the library preparation. Identical samples prepared with different methods show highly varied levels of different miRNAs. Even so, many methods excelled in ease of use, lower input requirement, fraction of usable reads, and reproducibility across sites. These differences may help users select the most appropriate methods for their specific question of interest.
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http://dx.doi.org/10.7171/jbt.20-3102-001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953595PMC
July 2020

Systematic evaluation of RNA-Seq preparation protocol performance.

BMC Genomics 2019 Jul 11;20(1):571. Epub 2019 Jul 11.

Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Science Park, Smithville, TX, 78957, USA.

Background: RNA-Seq is currently the most widely used tool to analyze whole-transcriptome profiles. There are numerous commercial kits available to facilitate preparing RNA-Seq libraries; however, it is still not clear how some of these kits perform in terms of: 1) ribosomal RNA removal; 2) read coverage or recovery of exonic vs. intronic sequences; 3) identification of differentially expressed genes (DEGs); and 4) detection of long non-coding RNA (lncRNA). In RNA-Seq analysis, understanding the strengths and limitations of commonly used RNA-Seq library preparation protocols is important, as this technology remains costly and time-consuming.

Results: In this study, we present a comprehensive evaluation of four RNA-Seq kits. We used three standard input protocols: Illumina TruSeq Stranded Total RNA and mRNA kits, a modified NuGEN Ovation v2 kit, and the TaKaRa SMARTer Ultra Low RNA Kit v3. Our evaluation of these kits included quality control measures such as overall reproducibility, 5' and 3' end-bias, and the identification of DEGs, lncRNAs, and alternatively spliced transcripts. Overall, we found that the two Illumina kits were most similar in terms of recovering DEGs, and the Illumina, modified NuGEN, and TaKaRa kits allowed identification of a similar set of DEGs. However, we also discovered that the Illumina, NuGEN and TaKaRa kits each enriched for different sets of genes.

Conclusions: At the manufacturers' recommended input RNA levels, all the RNA-Seq library preparation protocols evaluated were suitable for distinguishing between experimental groups, and the TruSeq Stranded mRNA kit was universally applicable to studies focusing on protein-coding gene profiles. The TruSeq protocols tended to capture genes with higher expression and GC content, whereas the modified NuGEN protocol tended to capture longer genes. The SMARTer Ultra Low RNA Kit may be a good choice at the low RNA input level, although it was inferior to the TruSeq mRNA kit at standard input level in terms of rRNA removal, exonic mapping rates and recovered DEGs. Therefore, the choice of RNA-Seq library preparation kit can profoundly affect data outcomes. Consequently, it is a pivotal parameter to consider when designing an RNA-Seq experiment.
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http://dx.doi.org/10.1186/s12864-019-5953-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6625085PMC
July 2019

Structural basis of specific DNA binding by the transcription factor ZBTB24.

Nucleic Acids Res 2019 09;47(16):8388-8398

Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

ZBTB24, encoding a protein of the ZBTB family of transcriptional regulators, is one of four known genes-the other three being DNMT3B, CDCA7 and HELLS-that are mutated in immunodeficiency, centromeric instability and facial anomalies (ICF) syndrome, a genetic disorder characterized by DNA hypomethylation and antibody deficiency. The molecular mechanisms by which ZBTB24 regulates gene expression and the biological functions of ZBTB24 are poorly understood. Here, we identified a 12-bp consensus sequence [CT(G/T)CCAGGACCT] occupied by ZBTB24 in the mouse genome. The sequence is present at multiple loci, including the Cdca7 promoter region, and ZBTB24 binding is mostly associated with gene activation. Crystallography and DNA-binding data revealed that the last four of the eight zinc fingers (ZFs) (i.e. ZF5-8) in ZBTB24 confer specificity of DNA binding. Two ICF missense mutations have been identified in the ZBTB24 ZF domain, which alter zinc-binding cysteine residues. We demonstrated that the corresponding C382Y and C407G mutations in mouse ZBTB24 abolish specific DNA binding and fail to induce Cdca7 expression. Our analyses indicate and suggest a structural basis for the sequence specific recognition by a transcription factor centrally important for the pathogenesis of ICF syndrome.
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http://dx.doi.org/10.1093/nar/gkz557DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895263PMC
September 2019

Collagen-rich airway smooth muscle cells are a metastatic niche for tumor colonization in the lung.

Nat Commun 2019 05 13;10(1):2131. Epub 2019 May 13.

Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA.

Metastases account for the majority of cancer deaths. While certain steps of the metastatic cascade are well characterized, identification of targets to block this process remains a challenge. Host factors determining metastatic colonization to secondary organs are particularly important for exploration, as those might be shared among different cancer types. Here, we showed that bladder tumor cells expressing the collagen receptor, CD167a, responded to collagen I stimulation at the primary tumor to promote local invasion and utilized the same receptor to preferentially colonize at airway smooth muscle cells (ASMCs)-a rich source of collagen III in lung. Morphologically, COL3-CD167a-driven metastatic foci are uniquely distinct from typical lung alveolar metastatic lesions and exhibited activation of the CD167a-HSP90-Stat3 axis. Importantly, metastatic lung colonization could be abrogated using an investigational drug that attenuates Stat3 activity, implicating this seed-and-soil interaction as a therapeutic target for eliminating lung metastasis.
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http://dx.doi.org/10.1038/s41467-019-09878-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6513865PMC
May 2019

PRMT1 loss sensitizes cells to PRMT5 inhibition.

Nucleic Acids Res 2019 06;47(10):5038-5048

Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA.

PRMT5 is an arginine methyltransferase that accounts for the vast majority of the symmetric methylation in cells. PRMT5 exerts its function when complexed with MEP50/WDR77. This activity is often elevated in cancer cells and correlates with poor prognosis, making PRMT5 a therapeutic target. To investigate the PRMT5 signaling pathway and to identify genes whose loss-of-function sensitizes cancer cells to PRMT5 inhibition, we performed a CRISPR/Cas9 genetic screen in the presence of a PRMT5 inhibitor. We identified known components of the PRMT5 writer/reader pathway including PRMT5 itself, MEP50/WDR77, PPP4C, SMNDC1 and SRSF3. Interestingly, loss of PRMT1, the major asymmetric arginine methyltransferase, also sensitizes cells to PRMT5 inhibition. We investigated the interplay between PRMT5 and PRMT1, and found that combinatorial inhibitor treatment of small cell lung cancer and pancreatic cancer cell models have a synergistic effect. Furthermore, MTAP-deleted cells, which harbor an attenuated PRMT5-MEP50 signaling pathway, are generally more sensitive to PRMT1 inhibition. Together, these findings demonstrate that there is a degree of redundancy between the PRMT5 and PRMT1 pathways, even though these two enzymes deposit different types of arginine methylation marks. Targeting this redundancy provides a vulnerability for tumors carrying a co-deletion of MTAP and the adjacent CDKN2A tumor suppressor gene.
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http://dx.doi.org/10.1093/nar/gkz200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6547413PMC
June 2019

USP22 controls multiple signaling pathways that are essential for vasculature formation in the mouse placenta.

Development 2019 02 22;146(4). Epub 2019 Feb 22.

Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA

USP22, a component of the SAGA complex, is overexpressed in highly aggressive cancers, but the normal functions of this deubiquitinase are not well defined. We determined that loss of USP22 in mice results in embryonic lethality due to defects in extra-embryonic placental tissues and failure to establish proper vascular interactions with the maternal circulatory system. These phenotypes arise from abnormal gene expression patterns that reflect defective kinase signaling, including TGFβ and several receptor tyrosine kinase pathways. USP22 deletion in endothelial cells and pericytes that are induced from embryonic stem cells also hinders these signaling cascades, with detrimental effects on cell survival and differentiation as well as on the ability to form vessels. Our findings provide new insights into the functions of USP22 during development that may offer clues to its role in disease states.
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http://dx.doi.org/10.1242/dev.174037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6398448PMC
February 2019

CARM1 methylates MED12 to regulate its RNA-binding ability.

Life Sci Alliance 2018 Oct 19;1(5):e201800117. Epub 2018 Sep 19.

Department of Epigenetics and Molecular Carcinogenesis, MD Anderson Cancer Center, The University of Texas, Smithville, TX, USA.

The coactivator-associated arginine methyltransferase (CARM1) functions as a regulator of transcription by methylating a diverse array of substrates. To broaden our understanding of CARM1's mechanistic actions, we sought to identify additional substrates for this enzyme. To do this, we generated CARM1 substrate motif antibodies, and used immunoprecipitation coupled with mass spectrometry to identify cellular targets of CARM1, including mediator complex subunit 12 (MED12) and the lysine methyltransferase KMT2D. Both of these proteins are implicated in enhancer function. We identified the major CARM1-mediated MED12 methylation site as arginine 1899 (R), which interacts with the Tudor domain-containing effector molecule, TDRD3. Chromatin immunoprecipitation-seq studies revealed that CARM1 and the methyl mark it deposits are tightly associated with ERα-specific enhancers and positively modulate transcription of estrogen-regulated genes. In addition, we showed that the methylation of MED12, at the R site, and the recruitment of TDRD3 by this methylated motif are critical for the ability of MED12 to interact with activating noncoding RNAs.
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http://dx.doi.org/10.26508/lsa.201800117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6238599PMC
October 2018

DNMT3L facilitates DNA methylation partly by maintaining DNMT3A stability in mouse embryonic stem cells.

Nucleic Acids Res 2019 01;47(1):152-167

Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA.

DNMT3L (DNMT3-like), a member of the DNMT3 family, has no DNA methyltransferase activity but regulates de novo DNA methylation. While biochemical studies show that DNMT3L is capable of interacting with both DNMT3A and DNMT3B and stimulating their enzymatic activities, genetic evidence suggests that DNMT3L is essential for DNMT3A-mediated de novo methylation in germ cells but is dispensable for de novo methylation during embryogenesis, which is mainly mediated by DNMT3B. How DNMT3L regulates DNA methylation and what determines its functional specificity are not well understood. Here we show that DNMT3L-deficient mouse embryonic stem cells (mESCs) exhibit downregulation of DNMT3A, especially DNMT3A2, the predominant DNMT3A isoform in mESCs. DNA methylation analysis of DNMT3L-deficient mESCs reveals hypomethylation at many DNMT3A target regions. These results confirm that DNMT3L is a positive regulator of DNA methylation, contrary to a previous report that, in mESCs, DNMT3L regulates DNA methylation positively or negatively, depending on genomic regions. Mechanistically, DNMT3L forms a complex with DNMT3A2 and prevents DNMT3A2 from being degraded. Restoring the DNMT3A protein level in DNMT3L-deficient mESCs partially recovers DNA methylation. Thus, our work uncovers a role for DNMT3L in maintaining DNMT3A stability, which contributes to the effect of DNMT3L on DNMT3A-dependent DNA methylation.
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http://dx.doi.org/10.1093/nar/gky947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6326784PMC
January 2019

Wwox deletion leads to reduced GABA-ergic inhibitory interneuron numbers and activation of microglia and astrocytes in mouse hippocampus.

Neurobiol Dis 2019 01 2;121:163-176. Epub 2018 Oct 2.

Department of Epigenetics and Molecular Carcinogenesis, Science Park, The University of Texas MD Anderson Cancer Center, Smithville, TX, United States. Electronic address:

The association of WW domain-containing oxidoreductase WWOX gene loss of function with central nervous system (CNS) related pathologies is well documented. These include spinocerebellar ataxia, epilepsy and mental retardation (SCAR12, OMIM: 614322) and early infantile epileptic encephalopathy (EIEE28, OMIM: 616211) syndromes. However, there is complete lack of understanding of the pathophysiological mechanisms at play. In this study, using a Wwox knockout (Wwox KO) mouse model (2 weeks old, both sexes) and stereological studies we observe that Wwox deletion leads to a significant reduction in the number of hippocampal GABA-ergic (γ-aminobutyric acid) interneurons. Wwox KO mice displayed significantly reduced numbers of calcium-binding protein parvalbumin (PV) and neuropeptide Y (NPY) expressing interneurons in different subfields of the hippocampus in comparison to Wwox wild-type (WT) mice. We also detected decreased levels of Glutamic Acid Decarboxylase protein isoforms GAD65/67 expression in Wwox null hippocampi suggesting lower levels of GABA synthesis. In addition, Wwox deficiency was associated with signs of neuroinflammation such as evidence of activated microglia, astrogliosis, and overexpression of inflammatory cytokines Tnf-a and Il6. We also performed comparative transcriptome-wide expression analyses of neural stem cells grown as neurospheres from hippocampi of Wwox KO and WT mice thus identifying 283 genes significantly dysregulated in their expression. Functional annotation of transcriptome profiling differences identified 'neurological disease' and 'CNS development related functions' to be significantly enriched. Several epilepsy-related genes were found differentially expressed in Wwox KO neurospheres. This study provides the first genotype-phenotype observations as well as potential mechanistic clues associated with Wwox loss of function in the brain.
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http://dx.doi.org/10.1016/j.nbd.2018.09.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7104842PMC
January 2019

Polycomb Repressive Complex 2 is essential for development and maintenance of a functional TEC compartment.

Sci Rep 2018 09 25;8(1):14335. Epub 2018 Sep 25.

Department of Epigenetics and Molecular Carcinogenesis, The University of Texas M.D. Anderson Cancer Center, Science Park, Smithville, Texas, 78957, USA.

Thymic epithelial cells (TEC) are essential for thymocyte differentiation and repertoire selection. Despite their indispensable role in generating functional T cells, the molecular mechanisms that orchestrate TEC development from endodermal progenitors in the third pharyngeal pouch (3 PP) are not fully understood. We recently reported that the T-box transcription factor TBX1 negatively regulates TEC development. Although initially expressed throughout the 3 PP, Tbx1 becomes downregulated in thymus-fated progenitors and when ectopically expressed impairs TEC progenitor proliferation and differentiation. Here we show that ectopic Tbx1 expression in thymus fated endoderm increases expression of Polycomb repressive complex 2 (PRC2) target genes in TEC. PRC2 is an epigenetic modifier that represses gene expression by catalyzing trimethylation of lysine 27 on histone H3. The increased expression of PRC2 target genes suggests that ectopic Tbx1 interferes with PRC2 activity and implicates PRC2 as an important regulator of TEC development. To test this hypothesis, we used Foxn1 to delete Eed, a PRC2 component required for complex stability and function in thymus fated 3 PP endoderm. Proliferation and differentiation of fetal and newborn TEC were disrupted in the conditional knockout (Eed) mutants leading to severely dysplastic adult thymi. Consistent with PRC2-mediated transcriptional silencing, the majority of differentially expressed genes (DEG) were upregulated in Eed TEC. Moreover, a high frequency of Eed DEG overlapped with DEG in TEC that ectopically expressed Tbx1. These findings demonstrate that PRC2 plays a critical role in TEC development and suggest that Tbx1 expression must be downregulated in thymus fated 3 PP endoderm to ensure optimal PRC2 function.
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http://dx.doi.org/10.1038/s41598-018-32729-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6156232PMC
September 2018

Linking prostate cancer cell AR heterogeneity to distinct castration and enzalutamide responses.

Nat Commun 2018 09 6;9(1):3600. Epub 2018 Sep 6.

Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA.

Expression of androgen receptor (AR) in prostate cancer (PCa) is heterogeneous but the functional significance of AR heterogeneity remains unclear. Screening ~200 castration-resistant PCa (CRPC) cores and whole-mount sections (from 89 patients) reveals 3 AR expression patterns: nuclear (nuc-AR), mixed nuclear/cytoplasmic (nuc/cyto-AR), and low/no expression (AR). Xenograft modeling demonstrates that AR CRPC is enzalutamide-sensitive but AR CRPC is resistant. Genome editing-derived AR and AR-knockout LNCaP cell clones exhibit distinct biological and tumorigenic properties and contrasting responses to enzalutamide. RNA-Seq and biochemical analyses, coupled with experimental combinatorial therapy, identify BCL-2 as a critical therapeutic target and provide proof-of-concept therapeutic regimens for both AR and AR CRPC. Our study links AR expression heterogeneity to distinct castration/enzalutamide responses and has important implications in understanding the cellular basis of prostate tumor responses to AR-targeting therapies and in facilitating development of novel therapeutics to target AR PCa cells/clones.
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http://dx.doi.org/10.1038/s41467-018-06067-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6127155PMC
September 2018

DNMT3A and TET1 cooperate to regulate promoter epigenetic landscapes in mouse embryonic stem cells.

Genome Biol 2018 07 12;19(1):88. Epub 2018 Jul 12.

Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX, 77030, USA.

Background: DNA methylation is a heritable epigenetic mark, enabling stable but reversible gene repression. In mammalian cells, DNA methyltransferases (DNMTs) are responsible for modifying cytosine to 5-methylcytosine (5mC), which can be further oxidized by the TET dioxygenases to ultimately cause DNA demethylation. However, the genome-wide cooperation and functions of these two families of proteins, especially at large under-methylated regions, called canyons, remain largely unknown.

Results: Here we demonstrate that DNMT3A and TET1 function in a complementary and competitive manner in mouse embryonic stem cells to mediate proper epigenetic landscapes and gene expression. The longer isoform of DNMT3A, DNMT3A1, exhibits significant enrichment at distal promoters and canyon edges, but is excluded from proximal promoters and canyons where TET1 shows prominent binding. Deletion of Tet1 increases DNMT3A1 binding capacity at and around genes with wild-type TET1 binding. However, deletion of Dnmt3a has a minor effect on TET1 binding on chromatin, indicating that TET1 may limit DNA methylation partially by protecting its targets from DNMT3A and establishing boundaries for DNA methylation. Local CpG density may determine their complementary binding patterns and therefore that the methylation landscape is encoded in the DNA sequence. Furthermore, DNMT3A and TET1 impact histone modifications which in turn regulate gene expression. In particular, they regulate Polycomb Repressive Complex 2 (PRC2)-mediated H3K27me3 enrichment to constrain gene expression from bivalent promoters.

Conclusions: We conclude that DNMT3A and TET1 regulate the epigenome and gene expression at specific targets via their functional interplay.
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http://dx.doi.org/10.1186/s13059-018-1464-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6042404PMC
July 2018

Role of autophagy in sevoflurane-induced neurotoxicity in neonatal rat hippocampal cells.

Brain Res Bull 2018 06 29;140:291-298. Epub 2018 May 29.

Department of Anesthesiology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China. Electronic address:

Background: Sevoflurane has been extensively employed for induction and maintenance of general anesthesia. The effect of sevoflurane-induced apoptosis in developmental neurotoxicity has been appreciated for some time now, but the underlying mechanism of developmental neurotoxicity has not been established. The aim of our study is to evaluate the role of autophagy in sevoflurane-induced neurotoxicity through observing changes in the levels of autophagy in hippocampal neurons after exposure to sevoflurane.

Methods/materials: Primary cultured hippocampus neuronal cells were exposed to either 3.4% sevoflurane for 1 h (S group), 3 h (S group), 5 h (S group), or air (control group). We observed changes in autophagy proteins Beclin-1, LC3-II, p62, and Beclin-1mRNA, LC3mRNA and SQSTM1mRNA using Western Blot and QRT-PCR. We also determined the expression of LC3 using immunofluorescence staining, monitored the occurrence of autophagy using RFP-GFP-LC3 expression plasmid transient transfected hippocampal neuronal cells, detected the expression of LC3-II using siRNA Knockdown Beclin-1 and Atg5, and determined changes in cell apoptosis using Annexin V/PI staining and flow cytometry.

Results: After primary cultured hippocampal neuronal cells were exposed to 3.4% sevoflurane for 5 h, the expression level of Beclin-1 and LC3-II increased and p62 decreased in Western blotting. The expression of Beclin-1mRNA, LC3mRNA increased and SQSTM1mRNA decreased in QRT-PCR. LC3 increased with cell immunofluorescence staining, LC3 expression plasmid increased after mRFP-GFP-LC3 expression plasmid transient transfection and LC3-II decreased after transfection with siRNA Beclin-1 and siRNA Atg5. The apoptosis rate of primary cultured hippocampal neuronal cells increased in Annexin V/PI staining and flow cytometry analysis.

Conclusion: This study demonstrates that sevoflurane may induce hippocampal neuron autophagy in primary cultured hippocampal neuronal cell and that Beclin-1 and Atg5 are involved in the process of sevoflurane-induced autophagy. Exposure of sevoflurane may not only induce autophagy of hippocampal neurons but also activate the apoptosis of hippocampal neurons. Autophagy may play an important role in sevoflurane-induced neurotoxicity in primary cultured hippocampal neuronal cells.
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http://dx.doi.org/10.1016/j.brainresbull.2018.05.020DOI Listing
June 2018

Autophagy is involved in sevoflurane-induced developmental neurotoxicity in the developing rat brain.

Brain Res Bull 2018 06 24;140:226-232. Epub 2018 May 24.

Department of Anesthesiology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China. Electronic address:

Background: Sevoflurane can induce neonatal wide neurodegenerative and serious deficit to space learning tasks in rodents, however, the specific mechanism is still unclear. At present, the study tried to explore the possible role of autophagy in sevoflurane-induced neurotoxicity through observing the changes in the levels of autophagy in the newborn SD rat hippocampus tissue after sevoflurane exposure.

Methods: We used seventy-two SD rats of seven days receiving sevoflurane exposure to explore hippocampus neuron autophagy and apoptosis.

Results: Our results indicated that sevoflurane increased the levels of Beclin-1, microtubule-associated protein light chain 3II protein and decreased sequestosome 1 levels in a time-dependent manner by Western blot in the developing brain. These results were further substantiated by transmission electron microscopy, quantitative reverse transcription polymerase chain reaction, immunohistochemistry and immunofluorescence. Rapamycin, an activator of autophagy, increased the levels of Beclin-1and LC3-II protein, meanwhile, 3-methyladenine, an inhibitor of autophagy, decreased Beclin-1and LC3-II protein levels.

Conclusion: Taken together, autophagy may be involved in sevoflurane-induced developmental neurotoxicity and promoting protective autophagy may be a potential way of preventing developmental sevoflurane-induced neurotoxicity.
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http://dx.doi.org/10.1016/j.brainresbull.2018.05.014DOI Listing
June 2018

The arginine methyltransferase CARM1 represses p300•ACT•CREMτ activity and is required for spermiogenesis.

Nucleic Acids Res 2018 05;46(9):4327-4343

Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA.

CARM1 is a protein arginine methyltransferase (PRMT) that has been firmly implicated in transcriptional regulation. However, the molecular mechanisms by which CARM1 orchestrates transcriptional regulation are not fully understood, especially in a tissue-specific context. We found that Carm1 is highly expressed in the mouse testis and localizes to the nucleus in spermatids, suggesting an important role for Carm1 in spermiogenesis. Using a germline-specific conditional Carm1 knockout mouse model, we found that it is essential for the late stages of haploid germ cell development. Loss of Carm1 led to a low sperm count and deformed sperm heads that can be attributed to defective elongation of round spermatids. RNA-seq analysis of Carm1-null spermatids revealed that the deregulated genes fell into similar categories as those impacted by p300-loss, thus providing a link between Carm1 and p300. Importantly, p300 has long been known to be a major Carm1 substrate. We found that CREMτ, a key testis-specific transcription factor, associates with p300 through its activator, ACT, and that this interaction is negatively regulated by the methylation of p300 by Carm1. Thus, high nuclear Carm1 levels negatively impact the p300•ACT•CREMτ axis during late stages of spermiogenesis.
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http://dx.doi.org/10.1093/nar/gky240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5961101PMC
May 2018

The Effects of Leukocyte Filtration on Cell Salvaged Autologous Blood Transfusion on Lung Function and Lung Inflammatory and Oxidative Stress Reactions in Elderly Patients Undergoing Lumbar Spinal Surgery.

J Neurosurg Anesthesiol 2019 Jan;31(1):36-42

Department of Anesthesiology, The Children's Hospital, School of Medicine, Zhejiang University, Hangzhou, China.

Background: This study was designed to investigate the effects of leukocyte filtration of autologous salvaged blood on lung function, lung inflammatory reaction, and oxidative stress reaction in elderly patients undergoing lumbar spinal surgery.

Materials And Methods: Sixty elderly patients undergoing lumbar spinal surgery were randomly divided into 2 groups: Leukocyte Filter group and Control group. Serum levels of inflammatory markers including white blood cell and polymorphonuclear count, neutrophil elastase, serum surfactant protein A, methane dicarboxylic aldehyde, superoxide dismutase, interleukin (IL)-6, IL-8, tumor necrosis factor-α, and respiratory function markers including dynamic respiratory system compliance, oxygenation index, and respiratory index were measured immediately before induction of anesthesia (T0), immediately before blood transfusion (T1), and 1 (T2), 6 (T3), and 12 hours (T4) after end of blood transfusion.

Results: The Leukocyte Filter group had higher dynamic respiratory system compliance at T2, oxygenation index at T2 and T3, respiratory index and superoxide dismutase at T2, T3, and T4 than those in the Control group (P<0.05). The Leukocyte Filter group had lower white blood cell, polymorphonuclear count, neutrophil elastase, serum surfactant protein A, methane dicarboxylic aldehyde, IL-6, IL-8, and tumor necrosis factor-α at T2, T3, and T4 than those in the Control group (P<0.05). There were no significant differences in adverse reactions related specifically to blood transfusion or postoperative respiratory complications within 72 hours.

Conclusions: Salvaged autologous blood leukocyte filtration can improve ventilation, promote gas exchange and oxygenation, and inhibit lung inflammatory and oxidative stress reactions in elderly patients undergoing lumbar spinal surgery.
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http://dx.doi.org/10.1097/ANA.0000000000000495DOI Listing
January 2019

Histone modification profiling in breast cancer cell lines highlights commonalities and differences among subtypes.

BMC Genomics 2018 02 20;19(1):150. Epub 2018 Feb 20.

The Department of Epigenetics and Molecular Carcinogenesis, University of Texas Graduate School of Biomedical Sciences at Houston and The Center for Cancer Epigenetics, University of Texas M.D. Anderson Cancer Center, Houston, Texas, 77030, USA.

Background: Epigenetic regulators are frequently mutated or aberrantly expressed in a variety of cancers, leading to altered transcription states that result in changes in cell identity, behavior, and response to therapy.

Results: To define alterations in epigenetic landscapes in breast cancers, we profiled the distributions of 8 key histone modifications by ChIP-Seq, as well as primary (GRO-seq) and steady state (RNA-Seq) transcriptomes, across 13 distinct cell lines that represent 5 molecular subtypes of breast cancer and immortalized human mammary epithelial cells.

Discussion: Using combinatorial patterns of distinct histone modification signals, we defined subtype-specific chromatin signatures to nominate potential biomarkers. This approach identified AFAP1-AS1 as a triple negative breast cancer-specific gene associated with cell proliferation and epithelial-mesenchymal-transition. In addition, our chromatin mapping data in basal TNBC cell lines are consistent with gene expression patterns in TCGA that indicate decreased activity of the androgen receptor pathway but increased activity of the vitamin D biosynthesis pathway.

Conclusions: Together, these datasets provide a comprehensive resource for histone modification profiles that define epigenetic landscapes and reveal key chromatin signatures in breast cancer cell line subtypes with potential to identify novel and actionable targets for treatment.
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http://dx.doi.org/10.1186/s12864-018-4533-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5819162PMC
February 2018

Prognostic Power of a Tumor Differentiation Gene Signature for Bladder Urothelial Carcinomas.

J Natl Cancer Inst 2018 05;110(5):448-459

Department of Molecular and Cellular Biology, University of Texas MD Anderson Cancer Center, Smithville, TX.

Background: Muscle-invasive bladder cancers (MIBCs) cause approximately 150 000 deaths per year worldwide. Survival for MIBC patients is heterogeneous, with no clinically validated molecular markers that predict clinical outcome. Non-MIBCs (NMIBCs) generally have favorable outcome; however, a portion progress to MIBC. Hence, development of a prognostic tool that can guide decision-making is crucial for improving clinical management of bladder urothelial carcinomas.

Methods: Tumor grade is defined by pathologic evaluation of tumor cell differentiation, and it often associates with clinical outcome. The current study extrapolates this conventional wisdom and combines it with molecular profiling. We developed an 18-gene signature that molecularly defines urothelial cellular differentiation, thus classifying MIBCs and NMIBCs into two subgroups: basal and differentiated. We evaluated the prognostic capability of this "tumor differentiation signature" and three other existing gene signatures including the The Cancer Genome Atlas (TCGA; 2707 genes), MD Anderson Cancer Center (MDA; 2252 genes/2697 probes), and University of North Carolina at Chapel Hill (UNC; 47 genes) using five gene expression data sets derived from MIBC and NMIBC patients. All statistical tests were two-sided.

Results: The tumor differentiation signature demonstrated consistency and statistical robustness toward stratifying MIBC patients into different overall survival outcomes (TCGA cohort 1, P = .03; MDA discovery, P = .009; MDA validation, P = .01), while the other signatures were not as consistent. In addition, we analyzed the progression (Ta/T1 progressing to ≥T2) probability of NMIBCs. NMIBC patients with a basal tumor differentiation signature associated with worse progression outcome (P = .008). Gene functional term enrichment and gene set enrichment analyses revealed that genes involved in the biologic process of immune response and inflammatory response are among the most elevated within basal bladder cancers, implicating them as candidates for immune checkpoint therapies.

Conclusions: These results provide definitive evidence that a biology-prioritizing clustering methodology generates meaningful insights into patient stratification and reveals targetable molecular pathways to impact future therapeutic approach.
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http://dx.doi.org/10.1093/jnci/djx243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279371PMC
May 2018

Histone 2B-GFP Label-Retaining Prostate Luminal Cells Possess Progenitor Cell Properties and Are Intrinsically Resistant to Castration.

Stem Cell Reports 2018 01 21;10(1):228-242. Epub 2017 Dec 21.

Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, USA; Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA; Cancer Stem Cell Institute, Research Center for Translational Medicine, East Hospital, Tongji University, Shanghai 200120, PR China. Electronic address:

The existence of slow-cycling luminal cells in the prostate has been suggested, but their identity and functional properties remain unknown. Using a bigenic mouse model to earmark, isolate, and characterize the quiescent stem-like cells, we identify a label-retaining cell (LRC) population in the luminal cell layer as luminal progenitors. Molecular and biological characterizations show that these luminal LRCs are significantly enriched in the mouse proximal prostate, exhibit relative dormancy, display bipotency in both in vitro and in vivo assays, and express a stem/progenitor gene signature with resemblance to aggressive prostate cancer. Importantly, these LRCs, compared with bulk luminal cells, maintain a lower level of androgen receptor (AR) expression and are less androgen dependent and also castration resistant in vivo. Finally, analysis of phenotypic markers reveals heterogeneity within the luminal progenitor cell pool. Our study establishes luminal LRCs as progenitors that may serve as a cellular origin for castration-resistant prostate cancer.
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http://dx.doi.org/10.1016/j.stemcr.2017.11.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768933PMC
January 2018